Odor and molecular vibration: Neural coding of olfactory information

Wright, R. H.

doi:10.1016/0022-5193(77)90283-1

Cited by 74 publications

(50 citation statements)

References 18 publications

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“…Since Ogle's original proposal (1) for the vibration theory more than 140 y ago, the idea has been embraced by Dyson (4, 5), Wright (6)(7)(8), and Turin (9,10). However, we find that it does not apply to the human musk receptor OR5AN1 or the mouse thiol receptor MOR244-3, as shown by the clear absence of isotope effects with deorphaned human and mouse ORs on exposure to the specific deuterated, 13 C, and nonlabeled ligands for these ORs.…”

Section: Resultsmentioning

confidence: 99%

“…We assayed isotopomers of acetophenone (6) and benzaldehyde (7) in our system using cognate mouse ORs. Similar to the case of cyclopentadecanone, no significant difference was seen between nondeuterated and deuterated versions for all of the ORs tested (Fig.…”

Section: Response Of a Human Musk Or To Deuterated And Nondeuteratedmentioning

confidence: 99%

“…1C), as well as bis(methylthiomethyl) disulfide (9) and 9-d 10 , ligands for mouse receptor MOR244-3, which are notable for requiring copper for ligand binding and whose active site we have modeled (15,16). Deuterated compound (8-d 5 ) was prepared in several steps from dimethyl sulfoxide-d 6 and then oxidized to 9-d 10 ; these compounds had ∼100% d 5 and d 10 deuterium incorporation, respectively, according to GC-MS. When 8 and 9 were tested in the presence of 30 μM Cu 2+ , no differential receptor activity was seen, which was also the case for the other isotopomeric pairs tested ( Concerns Involving Impurities.…”

Section: Response Of a Human Musk Or To Deuterated And Nondeuteratedmentioning

confidence: 99%

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Implausibility of the vibrational theory of olfaction

Block

Jang

Matsunami

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

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The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/ deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and 13 C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d 30 lacks the 1,380-to 1,550-cm −1 IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.olfaction | isotopomers | cyclopentadecanone | muscone | electron transfer I n 1870, the British physician William Ogle wrote: "As in the eye and the ear the sensory impression is known to result not from the contact of material particles given off by the object seen or heard, but from waves or undulations of the ether or the air, one cannot but suspect that the same may be true in the remaining sense, and that the undulatory theory of smell. . . [may be] the true one" (1, 2). Of the 29 different "theories of odour" listed in the 1967 edition of The Chemical Senses (3), nine associate odor with vibrations, particularly those theories championed by Dyson (4, 5) and Wright (6-8). However, the premise that olfaction involves detection of vibrational frequencies of odorants remains highly speculative because neither the structures of the odorant receptors (ORs) nor the binding sites or the activation mechanisms triggered upon odorant binding to ORs have been established. In 1996-1997, Turin (9-12) elaborated on the undulatory theory of smell, as considered in more detail below, and suggested that a mechanism analogous to inelastic electron tunneling spectroscopy (13) may be involved, where tunneling electrons in the receptor probe the vibrational frequencies of odorants. In 2013, Gane et al. (14) In judging the plausibility...

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Section: Resultsmentioning

confidence: 99%

Section: Response Of a Human Musk Or To Deuterated And Nondeuteratedmentioning

confidence: 99%

Section: Response Of a Human Musk Or To Deuterated And Nondeuteratedmentioning

confidence: 99%

See 1 more Smart Citation

Implausibility of the vibrational theory of olfaction

Block

Jang

Matsunami

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

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“…may be possible to distinguish the scents of some very similar odorants, for example between those that are deuterated and non-deuterated. 26,30,37 It was suggested as early as 1938 that the sensing of vibrational spectra of molecules [38][39][40] -later proposed to occur via electron transfer 21,22 -could play an important role in olfaction, supplementing (rather than replacing) the existing lockand-key model. Recent work, focussing on constructing and exploring model systems that capture the important physical processes, 24,27 has shown that this is indeed a viable proposition.…”

Section: Introductionmentioning

confidence: 99%

Dissipation enhanced vibrational sensing in an olfactory molecular switch

Chęcińska

Pollock

Heaney

et al. 2015

The Journal of Chemical Physics

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Motivated by a proposed olfactory mechanism based on a vibrationally-activated molecular switch, we study electron transport within a donor-acceptor pair that is coupled to a vibrational mode and embedded in a surrounding environment. We derive a polaron master equation with which we study the dynamics of both the electronic and vibrational degrees of freedom beyond previously employed semiclassical (MarcusJortner) rate analyses. We show: (i) that in the absence of explicit dissipation of the vibrational mode, the semiclassical approach is generally unable to capture the dynamics predicted by our master equation due to both its assumption of one-way (exponential) electron transfer from donor to acceptor and its neglect of the spectral details of the environment; (ii) that by additionally allowing strong dissipation to act on the odorant vibrational mode we can recover exponential electron transfer, though typically at a rate that differs from that given by the Marcus-Jortner expression; (iii) that the ability of the molecular switch to discriminate between the presence and absence of the odorant, and its sensitivity to the odorant vibrational frequency, are enhanced significantly in this strong dissipation regime, when compared to the case without mode dissipation; and (iv) that details of the environment absent from previous Marcus-Jortner analyses can also dramatically alter the sensitivity of the molecular switch, in particular allowing its frequency resolution to be improved. Our results thus demonstrate the constructive role dissipation can play in facilitating sensitive and selective operation in molecular switch devices, as well as the inadequacy of semiclassical rate equations in analysing such behaviour over a wide range of parameters.

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“…There have been several tests of the previous iterations of the VTO, including odor blending (25,26) and isotope exchange (20,(27)(28)(29)(30); each of these methods-odor blending (11,18) and isotope exchange (11,31)-has been used to evaluate the modern VTO. Initial justifications of the VTO correlated characteristics of the vibrational spectra with olfactory perception (12), continued within ORs (32), and expanded into non-OR GPCRs (33)(34)(35)(36).…”

mentioning

confidence: 99%

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Hoehn

Nichols

McCorvy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Recently, an alternative theory concerning the method by which olfactory proteins are activated has garnered attention. This theory proposes that the activation of olfactory G protein-coupled receptors occurs by an inelastic electron tunneling mechanism that is mediated through the presence of an agonist with an appropriate vibrational state to accept the inelastic portion of the tunneling electron's energy. In a recent series of papers, some suggestive theoretical evidence has been offered that this theory may be applied to nonolfactory G protein- O lfaction-and other chemo-sensitive sensory processes-is an important information-gathering technique for organisms of many clades and kingdoms. Specifically, human olfaction is known to occur by activation of olfactory receptors (ORs)-a subclass of G protein-coupled receptors (GPCRs)-located within the nasal epithelium and mediating responses within the olfactory bulb, where it is encoded and conveys information to the amygdala, the orbitofrontal cortex, and the hippocampus (1, 2). The discovery and the cloning of ORs led to the joint 2004 Nobel Prize in Physiology and Medicine to Richard Axel and Linda Buck. (3) GPCRs are 7-helical transmembrane proteins, facilitating communication from extracellular ligand signals to the cellular interior through activation of (interior) G proteins, while maintaining the integrity of the membrane (4). GPCRs are activated by an appropriate agonist moving into the protein's orthosteric binding site, resulting in a conformational change within the helical bundle. This structural change leads to altered conformations of the intracellular loops that couple to appropriate signaling molecules within the cell, e.g., G proteins. A recent series of papers has experimentally determined activated/inactivated states through isotopic-tagged receptors with NMR spectroscopy (5-7). An additional work used molecular dynamics to provide structural insights into how the agonist may assist the interchange between conformations through several proposed peptide sidechain pathways by examining the structures of the activated and inactivated µ-opioid receptor (8). Additionally, photon-induced conformational changes in lightsensitive proteins have also been observed (9, 10).Recently, an iteration of the vibrational theory of olfaction (VTO)-suggested and advocated by Luca Turin (11, 12)-has arisen and has gained both supporters (13-16) and detractors (17, 18); the novelty of this incarnation of the VTO is ascribable to its nonthermal-and nonphoton-based mechanism. Turin's theory is a contemporary reincarnation of the more classical theory proposed by Dyson (19), Wright (20), and Wright and Serenius (21), where the activation of the olfactory receptor is performed-or sensitive to-the molecular vibrations of the olfactant. Dyson suggested that the molecular vibrations of the agonist were exactly responsible for the activation of the protein. These vibrations were entirely thermally excited, as no mechanism for photoexcitation is available within the body. Th...

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Odor and molecular vibration: Neural coding of olfactory information

Cited by 74 publications

References 18 publications

Implausibility of the vibrational theory of olfaction

Implausibility of the vibrational theory of olfaction

Dissipation enhanced vibrational sensing in an olfactory molecular switch

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

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